ABSTRACT
In a follow-up to our previously reported genome-wide association study of cutaneous basal cell carcinoma (BCC), we describe here several new susceptibility variants. SNP rs11170164, encoding a G138E substitution in the keratin 5 (KRT5) gene, affects risk of BCC (OR = 1.35, P = 2.1 x 10(-9)). A variant at 9p21 near CDKN2A and CDKN2B also confers susceptibility to BCC (rs2151280[C]; OR = 1.19, P = 6.9 x 10(-9)), as does rs157935[T] at 7q32 near the imprinted gene KLF14 (OR = 1.23, P = 5.7 x 10(-10)). The effect of rs157935[T] is dependent on the parental origin of the risk allele. None of these variants were found to be associated with melanoma or fair-pigmentation traits. A melanoma- and pigmentation-associated variant in the SLC45A2 gene, L374F, is associated with risk of both BCC and squamous cell carcinoma. Finally, we report conclusive evidence that rs401681[C] in the TERT-CLPTM1L locus confers susceptibility to BCC but protects against melanoma.
Subject(s)
Carcinoma, Basal Cell/genetics , Genetic Predisposition to Disease , Polymorphism, Single Nucleotide/genetics , Skin Neoplasms/genetics , Carcinoma, Basal Cell/complications , Carcinoma, Squamous Cell/genetics , Chromosomes, Human, Pair 7/genetics , Chromosomes, Human, Pair 9/genetics , Coronary Artery Disease/complications , Coronary Artery Disease/genetics , Genome-Wide Association Study , Humans , Keratin-5/genetics , Linkage Disequilibrium/genetics , Melanoma/pathology , Membrane Proteins/genetics , Molecular Sequence Data , Neoplasm Proteins/genetics , Skin Neoplasms/complicationsABSTRACT
The common sequence variants that have recently been associated with cancer risk are particular to a single cancer type or at most two. Following up on our genome-wide scan of basal cell carcinoma, we found that rs401681[C] on chromosome 5p15.33 satisfied our threshold for genome-wide significance (OR = 1.25, P = 3.7 x 10(-12)). We tested rs401681 for association with 16 additional cancer types in over 30,000 cancer cases and 45,000 controls and found association with lung cancer (OR = 1.15, P = 7.2 x 10(-8)) and urinary bladder, prostate and cervix cancer (ORs = 1.07-1.31, all P < 4 x 10(-4)). However, rs401681[C] seems to confer protection against cutaneous melanoma (OR = 0.88, P = 8.0 x 10(-4)). Notably, most of these cancer types have a strong environmental component to their risk. Investigation of the region led us to rs2736098[A], which showed stronger association with some cancer types. However, neither variant could fully account for the association of the other. rs2736098 corresponds to A305A in the telomerase reverse transcriptase (TERT) protein and rs401681 is in an intron of the CLPTM1L gene.
Subject(s)
Membrane Proteins/genetics , Neoplasm Proteins/genetics , Neoplasms/genetics , Polymorphism, Single Nucleotide , Telomerase/genetics , Aged , Carcinoma, Basal Cell/genetics , Case-Control Studies , Female , Gene Frequency , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Linkage Disequilibrium , Male , Middle Aged , Polymorphism, Single Nucleotide/physiology , Quantitative Trait Loci , Skin Neoplasms/geneticsABSTRACT
To search for new sequence variants that confer risk of cutaneous basal cell carcinoma (BCC), we conducted a genome-wide SNP association study of 930 Icelanders with BCC and 33,117 controls. After analyzing 304,083 SNPs, we observed signals from loci at 1p36 and 1q42, and replicated these associations in additional sample sets from Iceland and Eastern Europe. Overall, the most significant signals were from rs7538876 on 1p36 (OR = 1.28, P = 4.4 x 10(-12)) and rs801114 on 1q42 (OR = 1.28, P = 5.9 x 10(-12)). The 1p36 locus contains the candidate genes PADI4, PADI6, RCC2 and ARHGEF10L, and the gene nearest to the 1q42 locus is the ras-homolog RHOU. Neither locus was associated with fair pigmentation traits that are known risk factors for BCC, and no risk was observed for melanoma. Approximately 1.6% of individuals of European ancestry are homozygous for both variants, and their estimated risk of BCC is 2.68 times that of noncarriers.
Subject(s)
Carcinoma, Basal Cell/genetics , Chromosomes, Human, Pair 1/genetics , Genetic Predisposition to Disease , Melanoma/genetics , Mutation/genetics , Pigmentation/genetics , Skin Neoplasms/genetics , Adipose Tissue/metabolism , Adolescent , Adult , Aged , Aged, 80 and over , Aging , Alleles , Carcinoma, Basal Cell/diagnosis , Carcinoma, Squamous Cell/genetics , Chromosomal Proteins, Non-Histone/genetics , Chromosomal Proteins, Non-Histone/metabolism , Guanine Nucleotide Exchange Factors/genetics , Guanine Nucleotide Exchange Factors/metabolism , Humans , Middle Aged , Models, Genetic , Polymorphism, Single Nucleotide/genetics , Quantitative Trait, Heritable , RNA/metabolism , Skin Neoplasms/diagnosisABSTRACT
Fair color increases risk of cutaneous melanoma (CM) and basal cell carcinoma (BCC). Recent genome-wide association studies have identified variants affecting hair, eye and skin pigmentation in Europeans. Here, we assess the effect of these variants on risk of CM and BCC in European populations comprising 2,121 individuals with CM, 2,163 individuals with BCC and over 40,000 controls. A haplotype near ASIP, known to affect a similar spectrum of pigmentation traits as MC1R variants, conferred significant risk of CM (odds ratio (OR) = 1.45, P = 1.2 x 10(-9)) and BCC (OR = 1.33, P = 1.2 x 10(-6)). The variant in TYR encoding the R402Q amino acid substitution, previously shown to affect eye color and tanning response, conferred risk of CM (OR = 1.21, P = 2.8 x 10(-7)) and BCC (OR = 1.14, P = 6.1 x 10(-4)). An eye color variant in TYRP1 was associated with risk of CM (OR = 1.15, P = 4.6 x 10(-4)). The association of all three variants is robust with respect to adjustment for the effect of pigmentation.